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December 18, 2012

On December 14, FDA released a draft guidance document entitled “Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products” (“Enrichment Guidance”). The thirty-nine-page document was more than six years in the making and aims to provide “guidance to industry on enrichment strategies that can be used in clinical trials intended to support effectiveness and safety claims.” It also “defines several types of enrichment strategies, provides examples of various potential clinical trial designs, and discusses potential regulatory considerations when using enrichment strategies in clinical trials.” The Enrichment Guidance follows a June 21, 2012 article written by Bob Temple entitled “Enrichment Design Studies should Enhance Signals of Effectiveness” and is the product of years of research, papers, and presentations. It is a welcome step towards providing sponsors with insight into FDA’s thinking regarding enrichment strategies and will serve as an important guide for future clinical design.

Bob Temple, in a recent article, stated that “[w]hile enrichment won’t save a drug that doesn’t work, it will help find one that will.” Therefore, the draft guidance defines “enrichment” as “the prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population.”

Prognostic enrichment strategies which include “choosing patients with a greater likelihood of having a disease-related endpoint event (for event-driven studies) [such as a MACE event] or substantial worsening in condition (for continuous measurement endpoints).”

Predictive enrichment strategies which include “choosing patients more likely to respond to the drug treatment than other patients with the condition being treated.” This can result in large effect size, a smaller study population, and a more favorable benefit-risk relationship for the subset population. Selection of patients can be driven by factors including “a specific aspect of pathophysiology, past history of response, or a disease characteristic that is related in some manner to the study drug’s mechanism (e.g., genomic or proteomic factor).”

FDA notes that enrichment strategies must be careful to avoid issues relating to the generalizability and applicability of study results. Therefore, sponsors must consider whether potential enrichment strategies could be used in clinical practice and whether the treatment is useful in a population broader than the study population. The Enrichment Guidance also points out that enrichment studies must abide by established principles of well-controlled studies, control bias, and conserve studywise type I error. FDA also recommends that sponsors be explicit about enrichment designs in study protocols and reports and that they engage in early discussions with FDA on plans to use enrichment designs.

While FDA states that it is “very interested” in individualization of treatment and the efficiency of enrichment studies, it is also concerned that labeling adequately describe the studied population and do not overstate the benefit for the non-enrichment populations. Therefore, sponsors must carefully consider whether enrichment marker-negative populations should be studied, realizing that the enrichment strategy can have important implications to the labeling the drug will receive.

With regard to predictive enrichment, the question of whether non-marker patients can benefit is critical. FDA and sponsors must, therefore, consider the amount of information available on the marker-negative population, both before and after approval, risk-benefit for multiple groups, and whether the treatment is a critical advance for the enriched group such that “it would be generally unreasonable to delay approval for the enriched group, even if few data on the group without the enrichment factor were available and even if some off-label use were anticipated despite appropriate labeling.”

Importantly, FDA has signaled that many treatments will likely be required to show data on marker-negative population including risks to the marker-negative population, the relative size of the marker-negative population compared to the marker-positive population, and the likelihood of off-label usage in the marker-negative population. Therefore, FDA could require additional premarketing or postmarketing studies on these marker-negative populations.

FDA puts the Enrichment Guidance into perspective by concluding that, despite a number of concerns and limitations, it “is prepared to approve drugs studied primarily or even solely in enriched populations.”